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FGF8-FGFR1 Signaling Acts as a Niche Factor for Maintaining Undifferentiated Spermatogonia in the Mouse1
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) d8 X$ Y' u3 X# FPublished online before print October 30, 2014, doi: 10.1095/biolreprod.114.121012
6 V0 `0 Q8 i8 B, K. [6 oBiology of Reproduction December 1, 2014 vol. 91 no. 6 145# Q8 w& z/ G, J! i" M* `3 L- B6 m
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ABSTRACT
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1 A: E: @8 }% f# X& IIn mammalian testes, spermatogonial stem cells (SSCs) maintain spermatogenesis over a long period of time by undergoing self-renewal and differentiation. SSCs are among the most primitive of spermatogenic cells (undifferentiated spermatogonia), and their activities are strictly regulated by extrinsic niche factors. However, the factors that constitute a testicular niche remain poorly understood. In this study, we demonstrate that fibroblast growth factor (FGF) signaling maintains undifferentiated spermatogonia through activating ERK1/2 signaling in vivo. Undifferentiated spermatogonia comprise GFRA1+ and NANOS3+ subpopulations, which are likely to undergo self-renewal and enter the differentiation pathway, respectively. In the testis, Fgfr1 was expressed in the entire population of undifferentiated spermatogonia, and deleting FGFR1 in spermatogenic cells partially inactivated ERK1/2 and resulted in reduced numbers of both GFRA1+ and NANOS3+ cells. In addition, Fgf8 was expressed in spermatogenic cells, and loss- and gain-of-function models of FGF8 demonstrated that FGF8 positively regulated the numbers of undifferentiated spermatogonia through FGFR1, particularly among NANOS3+ cells. Finally we show a possible involvement of FGF signaling in the reversion from NANOS3+ into GFRA1+ undifferentiated spermatogonia. Taken together, our data suggest that FGF signaling is an important component of the testicular niche and has a unique function for maintaining undifferentiated spermatogonia.! Y: y2 }5 T7 |! R! X$ P5 f
' y; f4 T2 j i# X5 t: X: e. L2 PKey words: developmental biology knockout model Sertoli cells signal transduction spermatogonial stem cells transgenic model1 f k% E) N& R* ? x
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